Aminoalkanol derivatives of piperazines



United States Patent 3,190,883 7 AMINOALKANOL DERIVATIVES 0F PIPERAZINESCharles F. Geschickter, Lon-ton, and John S. Pierce, Richmond, Va.,Ebenezer E. Reid, Baltimore, Md., and Yiug H. Chen, Richmond, Va.,assignors to The Geschickter Fund for Medical Research, Inc.,Washington, D.C., a corporation of New York No Drawing. Filed Oct. 5,1962, Ser. No. 228,743 11 Claims. (Cl. 260-268) The present inventionrelates to the preparation and uses of a novel set of polyaminoalkanols'and, more specifically, it relates to a group of polyaminoalkanols whichcan be represented by the following generic formula:

, wherein B is a member of the group consisting of (l) morpholino, (2)pyrrolidino, (3) piperidino, (4) methylcyclohexylamino, (5) piperazinoof the structure Y-N N- Y wherein Y is an alkyl radical of 1 to 6carbons, and (6) wherein R and R each is an alkyl radical of 1 to 4carbons; wherein X is a member of the group consisting of H and CH0; andn is a number from 0 to 4 both in structures (I) and (II); no carbon inthe piperazine rings of structures (I) and (11) having more than onemethyl group attached to it.

The compounds of the present, invention are valuable intermediates forthe formation of useful industrial and pharmaceutical chemicals. Animportant specific use of these compounds is as intermediates to formuseful fungicidal agents. In addition, the compounds of the presentinvention are relatively non-toxic and are active pharmacologically. Theparticular clinical uses depend on the structure of (I), as B, X and nvary.

A primary object of the present invention is to provide novelpolyarninoalkanols having both pharmaceutical and non-pharmaceuticalutility.

Another important object of the present invention is to provide novelpolyaminoalkanols having the general formula B-CHgCHOHCH N N-X whereinB, n and X have the values previously mentioned.

Still another important object of the present invention is to providecompounds which are low in toxicity and are useful medicinally, aspecific such medicinal utility being as motor relaxants.

ice

A further object f the present invention is to provide useful chemicalintermediates of the structure B-CH CHOHCHzN NH (III) wherein B and nhave the values previously mentioned. A still further object of thepresent invention is to provide intermediates of the structure wherein Band n have the values previously mentioned and which can be hydrolyzedto form the compounds of structure (III).

Another object of the present invention is to provide intermediates ofstructure (III) containing the active group NH, which reacts with Lewisacids, as halohydrins, epoxides, high molecular weight acid chloridesand other Lewis acids well known to those skilled in the art of organicsynthesis to yield useful industrial and pharmaceutical chemicals. is inthe formation of useful chelating agents.

A still further object of the present invention is to provideintermediates for the formation of compounds of the structure wherein Band n have the values previously mentioned, which combine with Cu++ toform useful fungicidal agents.

Another object of the present invention is to provide intermediates toreact with compounds such as BrCH CHOH (CH COOCH to form compounds whichcan be hydrolyzed'with sodium hydroxide to form sodium salts of highmolecular Weight B-GHzQHOHOHN None Patented June 22', 1965- Anapplication of this object (III) (Hydrolysis also can be brought aboutby heating compounds of structure (IV) with aqueous-alcoholic alkali.)

Equation 4 can be used for the preparation of all compounds of structure(IV), Equation 6 being preferred for the preparation of such compoundswhen B is (CH N. All compounds of structure (III) can be prepared byEquations 7 and 8. Syntheses involving Equations 3, 4, 5, 6, 7 and 8 aregiven in the illustrative examples.

The N-methylpiperazine used in the present specification was purchased.The other N-alkylpiperazines were synthesized, either by reaction of thealkyl halide (usually bromide) with the piperazine or the reaction ofthe alkyl halide with the N-formylpiperazine and the cleavage of theformyl group.

' The N-formylpiperazines used in the examples were prepared by thereaction of approximately equimolar quantities of the piperazine andmethyl formate, by the method of Kiichi et a1. [(1) Kiichi Fujii, KoichiTomino and Hiroyasu Watanbe, J. Pharm. Soc. Japan, 74, 1049-51 (1954);CA. 49, 11666f (1955)]. In the reaction of piperazine,2-methylpiperazine, cis-2,S-dimethylpiperazine and2,6-dirnethylpiperazine no solvent was used. For the formylation oftrans-2,S-dimethylpiperazine and 2,3,5,6- tetramethylpiperazine,isopropanol was used as solvent.

The epihydrinamines,

are prepared by reaction of approximately equimolar quantities ofsecondary amine (B-H) and epichlorohydrin, preferably in the presence ofa trace of water, and by treatment of the reaction product withconcentrated alkali (viz., approximately 33% NaOH solution). Whenextremely reactive amines, such as pyrrolidine or N-methylpiperazine areused, external cooling, vigorous stirring and slow addition of reagentstend to increase the yield of epihydrinamine. Since some of theepihydrinamines may react almost explosively when distilled in thepresence of traces of certain impurities, the preparation anddistillation of two typical epihydrinamines are set forth in theexamples.

While it is possible to use either crude or distilled epihydrinamines inEquations 4 and 8, better results are obtained when the distilledepoxide is used. In the illustrative examples, distilled epihydrinamineswere used except when otherwise indicated. None of the epihydrinaminesof the structure CH a) O H HO- EXAMPLE 1 To a solution of 2 ml. of waterin 50.0 g. (0.50 mole) of N-methylpiperazine at about 20 C. was added47.0 g. (0.51 mole) of epichlorohydrin over a period of one hour. Thereaction mixture, kept at a temperature of about 26, was stirred for 3additional hours. A solution of 25 g. (0.62 mole) of sodium hydroxide in50 ml. of water was added in 1.5 hours, the temperature being kept below30.

The upper layer was separated by decantation and was extracted withportions of ether, 200 ml. and m1., respectively. The combined extractswere dried over potassium hydroxide pellets in the refrigerator for 18hours. The supernatant liquid was decanted and filtered into ashort-necked distilling flask. On vacuum evaporation of the ether andvacuum distillation of the residue, there was obtained 33.9 g. of3-(4-methylpiperazino)-1,2-epoxypropane, boiling at -117 at 22 mm.pressure. (Calcd. for C H N O: N, 18.0%. Found, 17.5%.)

EXAMPLE 2 To a mixture of 46.7 g. (0.50 mole) of epichlorohydrin and 1.5ml. of water was added, over a period of 1.5 hours, 36.5 g. (0.51 mole)of pyrrolidine, the temperature being kept at about 12. The reactionmixture was stirred for four additional hours, the temperature beingmaintained at 2022. A cold solution of 24 g. (0.60 mole) of sodiumhydroxide in 50 ml. of water was added slowly and stirring was continuedfor'another hour. The reaction mixture had two layers, each of which wasvery soluble in water. The upper layer was decanted off and the lowerlayer was extracted with 300 ml. of ether. The ethereal solution wascombined with the upper layer and dried over potassium hydroxide pelletsin the refrigerator for 18 hours. The ether solution was vacuumevaporated and the residue was vacuum distilled from a hot water bath.The yield of 3-pyrrolidino-1,2-epoxypropane, boiling at 6870 at 13.3mm., was 29.0 g. (Calc. for C H NO: N, 11.0%. Found 11.0%.)

As stated previously, either crude or distilled epihydrinamines can beused in Equations 4 and 8. The crude epihydrinamines can be used inether solution or the ether can be evaporated, leaving theepihydriuamine as residual liquid.

Compounds of structure (IV) can be prepared by the following generalmethod:

In a typical preparation, an equimolar mixture of an epihydrinamine ofstructure 0 B-CH2O CH,

and a formylpiperazine of the structure Hi l-N NH is allowed to stand atroom temperature for a few days and is heated for approximately 10 hourson a steam bath. The reaction product of structure (IV) is obtained byvacuum distillation. The reaction of the epihydrinamine and theformylpiperazine is carried out with a solvent, such as- 95% ethanol, orwith no solvent. When ethanol is used as a solvent for the initialreaction, it can be removed by evaporation in the process of heating thereaction mixture.

This procedure for preparing the compounds of structure IV (exemplifiedin Equation 4) is illustrated in Examples 3-18 which follow.

EXAMPLE 3 A mixture of 6.4 g. (0.05 mole) of l-formyl-S-mthylpiperazine(with some 1-formyl-Z-methylpiperazine) and 6.5 g. (0.05 mole) of3-diethylamino-1,2-epoxypropane was allowed to stand at room temperaturefor four days. The mixture was heated on a steam bath for hours and wasvacuum distilled. The yield of1-formy1-4-(3-diethylamino-Z-hydroxypropyl)-3-methylpiperazine (and the2-methyl isomer), boiling at 165-166 at 0.80 mm. pressure, was 7.0 g.

EXAMPLE 4 1 formyl-4-(3-piperidino-2-hydroxypropyl)piperazine,

boiling at 187190 at 0.60 mm. pressure, was obtained in yield of 40percent, by allowing a mixture of equimolar quantities ofN-formylpiperazine and 3-piperidino-1,2- epoxypropane to stand for twoweeks, heating on a water bath for 8 hours and vacuum distillation.

EXAMPLE 5 EXAMPLE ,6

l-formyl-4-(3-rnorpholino 2 hydroxypropyl)-cis-2,5- dimethylpiperazine,boiling at-178-180 at 0.20 mm. pressure, was obtained in a yield of 55percent by vacuum distillation of the reaction product of equimolaramounts of 1-formyl-cis-2,S-dimethylpiperazine and 3-morpholino-1,2-epoxypropane, after 7 days standing and 14 hours heating on a steambath.

EXAMPLE 7 A mixture of 193.5 g. (1.50 moles) of 3-diethylamino-1,2-epoxypropane and 227 g. (1.59 moles) ofl-formylcis-2,S-dimethylpiperazine was stirred mechanically in a literround bottom flask for 4 hours, as the temperature was maintained below35. The stirring was continued overnight, as the flask was cooled in atap water bath. The mixture Was allowed to stand at room temperature for7 days and was heated at 75 for 6 hours and at 63 for hours. Thereaction mixture was subjected to vacuum distillation. The yield of1-formyl-4-(3 diethylamino- Z-hydroxypropyl)-cis-2,S-dimethylpiperazine,boiling at 144146 at 0.18 mm. pressure, was 140 g.

EXAMPLE 8 A mixture of 7.8 g. (0.051 mole) of3-(2-methylpiperidino)-1,2-epoxypropane,, 6.4 g. (0.05 mole) of 1-formylS-methylpiperazine (with a trace of isomer) and 10 ml. of 95% ethanolwas allowed to stand at room temperature for one week and then washeated on a water bath for 8 hours. The resulting reaction mixture wasdistilled under reduced pressure to yield 6.8 g. of

CH 3 7 011,611 dH-on,

Cfig NCH CHOHCH2N NCHO CHRCHE CHQCH 6 (with a trace of Z-methyl isomer)boiling at 198-200" at 0.75 mm! pressure.

' EXAMPLE 9 A mixture of14.2 g. (0.12 mole) of N-formylpiperazine, 17.2g. (0.12 mole) of 3-morpho1ino-1,2-epoxypropane and 50 ml. of percentethanol was allowed to stand for 5 days and then was heated atapproximately 75 for 8 hours. On vacuum distillation, 1-forrnyl-4- (3-morpholino-2-hydroxypropyl)piperazine, boiling at 172- 175 at 0.15 mm.pressure, was obtained in a yield of 15.5 g.

EXAMPLE 10 A mixture of 10.0 g. (0.088 mole) of N-formylpipenazine and15.3 g. (0.09 mole) of 3-methylcyclohexylamino-1,2-epoxypropane wasallowed to stand at room temperature for two weeks and then was heatedon a steam bath for 8 hours. The reaction mixture was distilled underreduced pressure. There was obtained 7.0 g. of 1formyl-4-(3-methylcyclohexylamino 2-hydroxypropyl)- piperazine, boilingat 218-220 at 0.80 mm. pressure.

EXAMPLE 1 1 A mixture of 6.4 g. (0.05 mole) ofl-form'yl-S-methylpiperazine (with some 1-formyl-Z-methylpiperazine) and7.0 g. (0.055 mole) of 3-pyrrolidino-1,2-epoxypropane was allowed tostand for 17 days and then was heated on a steam bath for 8 hours. Onvacuum distillation, 4 g. of1-formyl-4-(3-pyrro1idino-2-hydroxypropyl)-3-methylpiperazine (with some1-formy1-4-(3-pyrrolidino-2-hydroxypropyl)-2-rnethylpiperazine) wasobtained, boiling at 187189 at 0.90 mm. pressure.

EXAMPLE 12 On vacuum distillation, 7.5 g. of 1-forrnyl-4-[3-(2-methylpiperidino)-2-hydroxypropyl]-trans-2,5 dimethylpiperazine, boilingat 187-190 at 0.35 mm. pressure, was obtained from the reaction mixtureof 7.1 g. (0.05 mole) of 1-formyl-trans-2,S-dimethylpiperazine and 8.8g. (0.057 mole) of 3-(2-methylpiperidino)-1,2-epoxypropane, which wasmixed, allowed to stand for 10 days and heated on a steam bath for 12hours.

EXAMPLE 13 A mixture of 8.5 g. (0.050 mole) of 1-formyl-2,3,5,6-

tetramethylpiperazine and 7.5 g. (0.052 mole) of3-monpholino-1,2-epoxypropane was let stand for 2 weeks at roomtemperature and then was heated on a steam bath for 20 hours. On vacuumdistillation, 1-formyl-4-(3- morpholino-2-hydroxypropyl)-2,3,5,6tetramethylpiper azine, boiling at -168 at 0.15 mm. pressure, wasobtained in a yield of 4.0 g.

EXAMPLE 15 A mixture of 11.4 g. (0.10 mole) of N-formylpiperazine, 18.5g. (0.10 mole) of 3-(di-n-buty1amino)-1,2-

epoxypropane and 2 drops of water was allowed to stand.

for one week and then was heated on a steam bath for 10 hours. Thereaction mixture, on vacuum distillation, yielded 16.5 g. of1-formyl-4-[3- di-n-butylamino)-2-hydroxypropyl]piperazine, boiling at168470 at 0.18 mm. pressure.

7 EXAMPLE 16 l formyl-4-[3-(4-methylpiperidino)-2-hydroxypropyl]-cis-2,S-dimethylpiperazine, boiling at 185-187" at 0.30 mm. pressure,was obtained in a yield of 53% by reaction of equimolar quantities of1-formyl-cis-2,5-dimethylpiperazine and 3(4-methylpiperidino)-1,2-epoxypropane.

EXAMPLE 17 A mixture of 11.0 g. (0.077 mole) of 1-formyl-3,5-dimethylpiperazine (containing traces of 1-formyl-2,6-dimethylpiperazine) and 10.0 g. (0.078 mole) of3-diethylamino-1,2-epoxypropane was allowed to stand for two weeks andthen was heated on a steam bath for 8 hours. The reaction mixture wasdistilled under reduced pressure. The yield of1-formyl-4-(3-diethylarnino-2-hydroxypropyl)-3,5-dimethylpiperazine(with traces of 1- formyl-4-(3-diethylamino-2-hydroxypropyl)-2,6dimethylpiperazine), boiling at 170-172 at 0.75 mm., was 6.0 g.

EXAMPLE 18 To 11.4 g. (0.08 mole) of 1-formyl-cis-2,S-dimethylpiperazinewas added 20.3 g. (approximately 0.08 mole) of crude3-(4-hexyl-cis-2,S-dimethylpiperazine)-1,2-epoxypropane. The reactionmixture was shaken frequently and was allowed to stand for 15 days. Itthen was heated for 12 hours at approximately 70. On distillation, 10 g.of 1-formyl-4-'[3-(4-n-hexyl-cis 2,5dimethylpiperazine)-2-hydroxypropyl]-cis-2,S-dimethylpiperazine,

OH; CH;

aHiaN NCHzCHOHCHzN NCHO CH: CH;

015 cis boiling at approximately 216-210 at 0.35 mm., was obtained.[Calcd. for C H N O (titrable nitrogen): N, 10.60. Found, 10.80.]

The crude epihydrinamine,

$113 CHI-Cg:

N CH2CHCH; CHzI H CH3 cis was prepared as follows:

To 111 g. (0.56 mole) of l-hexyl-cis-2,5-dimethylpiperazine was added 56g. (0.60 mole) of epichlorohydrin. The reaction mixture was cooled in anice bath and was let stand at room temperature for 6 days. Then 26 g.(0.65 mole) of sodium hydroxide, in 30 ml. of water, was added, themixture was shaken thorougifly and allowed to stand for 2 days. Thereaction mixture then was diluted with 100 ml. of water and wasextracted with two 400 ml. portions of ether. The ether solution wasdried over potassium hydroxide pellets for days in the refrigerator. Onevaporation of the ether in a rotary evaporator at room temperature,there was obtained 114 g. of oil, crude1-(2,3-epoxypropyl)-4-n-hexyl-cis-2,3-dimethylpiperazine.

The following general procedure, with slight modification, which followsthe steps of Equations 5 and 6, is applicable to the preparation of allthe compounds of structure (IV) of the present specification.

. To a stirred solution of formylpiperazine of the structure Hah.

in approximately five volumes of ethanol, a quantity of epichlorohydrinequimolar to the formylpiperazine is added slowly. The reaction mixtureis stirred for about three hours, the temperature being kept at 2527. Asolution of 50% aqueous sodium hydroxide, containing base approximately1.25 times the number of moles of the formylpiperazine, is added slowlywith stirring. The stirring is continued for about one hour. A quantityof amine of structure B-H approximately double the molar quantity of theformylpiperazine is added with cooling and stirring. The mixture isallowed to stand at room temperature overnight and is heated gently on asteam bath or sand bath for approximately 8 hours. The reaction productof structure (IV) is obtained by vacuum distillation. Illustrations ofthis procedure are set forth in Examples 19-22.

EXAMPLE 19 To a stirred solution of 28.5 g. (0.20 mole) ofl-formylcis-2,S-dimethylpiperazine in 150 ml. of 95 percent ethanol,18.8 g. (0.20 mole) of epichlorohydrin was added slowly. The reactionmixture was stirred for 3.5 hours, the temperature being kept at 25-27".Then a solution of 10 g. of sodium hydroxide, dissolved in 20 ml. ofwater, was added slowly and stirring was continued for one hour. To thisreaction mixture 50 ml. of dimethylamine (25 percent in water) wasadded, with cooling and stirring, the temperature being kept at 32 for1.5 hours. The reaction mixture was filtered and the product,1-formyl-4(3-dimethylamino-Z-hydroxypropyl)- cis-2,S-dimethylpiperazine,boiling at 152154 at 9 mm. pressure, was obtained in a yield of 22% inan aliquot sample, on vacuum evaporation and vacuum distillation of theresidue.

EXAMPLE 20 A mixture of 17.2 g. (0.10 mole) of 1-formy1-2,3,5,6-tetramethylpiperazine and 9.3 g. (0.10 mole) of epichlorohydrin wasallowed to stand for one week, with frequent mixing. The reactionmixture was dissolved in 30 ml. of 95 percent ethanol and 15 ml. ofl-butanol was added. The reaction mixture was evaporated to low volumein a vacuum evaporator. The residual product was mixed vigorously withml. of 6 N sodium hydroxide solution and extracted with 100 ml. ofether. The ether solution was diluted with ether to 100 ml. and a 40 ml.portion was mixed with 50 ml. of dimethylamine (25 percent in water).The reaction mixture was allowed to stand overnight and then was heatedon a water bath for 24 hours. The reaction mixture was extracted with100 ml. of ether and the ether solution was filtered, the ether removedby vacuum evaporation and the residue was vacuum distilled. The yield of1-formyl-4-(3-dimethylamino-2-hydroxypropyl) 2,3,5,6tetramethylpiperazine, boiling at 142-145 at 0.45 mm., was 0.80 g.

EXAMPLE 21 h A mixture consisting of approximately 0.05 mole of crude1-formyl-4-(2,3-epoxypropyl)-cis-2,5-dimethylpiperazine and 0.10 mole ofdiethylamine with no solvent stood at room temperature for 12 hours andWas heated gently on a sand bath for 8 hours. The reaction mixture wasdistilled under reduced pressure. The yield of l-formyl-4-(3-diethylamino-2-hydroxypropyl) cis 2,5 dimethyl-' piperazine,boiling at 168-170 at 0.65 mm. pressure, was 10.0 g.

EXAMPLE 22 A mixture consisting of 0.05 mole of crude l-formyl-4-(2,3-epoxypropyl)-cis-2,5-dimethylpiperazine and 0.10 mole ofmorpholine stood at room temperature for 12 hours and was heated gentlyon a sand bath for 8 hours. The reaction mixture was vacuum distilled.The yield of Following are data relative to various compounds of 10 ingdosage intramuscularly once daily. The oral dosage of the pyrrolidinospecies should be 25-50 mg.

Such compounds are useful medicinally either as the free base or thetherapeutically acceptable acid addition structure (IV) made inaccordance with the present salt. The free bases are very soluble in 011base and the inventlon: acid addition salts are highly soluble in water.Examples Table A -3):: Hi2 NCH OHOHCHi-dfi B.P., Titrable Nitrogen, n B0. mm. Hg calcd. percent iound Di-isopropylamino 176-181 0. 40 10. 3210. Ethylbutylamino- 178180 0. 75 10. 32 9. 96 Di-n-butylamino. 168-1700. 18 9. 35 9. 26 Morpholino- 172175 0. 10. 89 10. 56 218220 O. 80 9. 889. 59 188-190 0. 60 11. 61 11. 48 187l90 0. 60 10. 97 10. 712-methylpiper 183184 O. 50 10. 40 10. 21 3-methylpiperidino..- l80-1820. 70 10. 40 10. 14 2,6-dimethyipiperidin 200206 0. 60 9. 89 9. 69Diethylamino 165-l66 0. 80 10. 88 I1. 18 Di-n-propylamino 192193 0. 709. 81 9. 67 Di-n-butylamino 190-192 0. 75 8. 94 8. 65 Morpholino.l84-186 0. 15 10. 32 10. 00 Methylcyclohexylaminm. 201 202 0. 9. 42 9.13 Pyrrolidi 187-l89 0. 90 10. 97 10. 93 Piporidino. 195196 0. 50 10.10. 38 2-methylpiperi lIlO 19S200 0.75 9. 88 9. 40 3-methylpiperidinol83185 O. 9. 88 I0. 01 l- 2,6-dimethylpiperidino- 204-207 0. 50 9. 42 9.2 Dimethylamino L--- 152-154 9. 00 11. 51 11. 57 2 Diethylamino 1681700. 10. 32 10. 00 x d0 144l46 0. 18 10.32 10. 31 170l72 0. 10. 32 10. 26178-179 0. 9. 35 9. 55 158-160 0. 20 9. 35 9. 47 178184 0. 50 9. 35 8.98 193195 0. 75 9. 35 9. 34 193195 0. 60 8. 55 8. 60 178180 O. 20 9. 829. 47 d0 1822l85 0. 25 9. 82 *10. 04 Methylcyclohexylaminm- 189-191 0.l5 8. 99 8. 68 Pyrrolidino a 173-175 0. i5 10. 40 10.68 2 Piperidino198200 0. 50 9. 88 10. 02 2 Z-methylpiperidino. 187190 0.35 9.42 9. 97 2d do 185186 0. 45 9. 42 8. 98 2 4-methylpipcridino 185-l87 0. 30 9. 429. 23 2 2,6-dimethylpiperidino 206208 0. 50 8. 99 9. 09 4 Dimethylamino142145 0. 45 10. 32 10. 00 4. do -168 0. 40 9.35 9. 46 4 Morpholino165-168 0. 15 8. 94 9. O3 4. Z-methylpiperidinc. 186-188 0. 25 8. 61 8.52 4- 3-methylpiperidino. 183-185 0. 45 8. G1 8. 24 4 4-methylpiperidino'172175 0. 25 8. 61 8. 00

NorE.-All compounds in Table A were prepared by Equation 4 unlessotherwise indicated.

"- Equation (6).

b Trans-2,5-dimethyl.

" Gis-2,5-dimethyl.

d 3,5-Dimethyl (or 2, G-methyl Titrated with perehloric acid in glacialacetic acid.

Not only are the compounds of structure (I) useful intermediates, aswill be discussed more specifically hereinafter, but many of them'are ofvalue clinically. For example, the compounds of structure pyrrolidino',these compounds may be administered orally three times daily in doses of30400 mg., or a correspondof therapeutically acceptable salts are thehydrochloride, sulfate, phosphate, acetate, lactate, ta-rtrate, citrate,maleate, etc. In general, those non-toxic salts of the free bases whichare soluble in water or other Well tolerated solvents are particularlyuseful for therapeutic purposes due to the ease of administration of thesalts in their dis solved form. In addition, other non-toxic salts mayalso be used.

Variations in the structure of (I), Within the limits just prescribed,give compounds particularly suited for special uses as muscle relaxants.For example, compounds of the structures (C HQgNCH OHOHCHgN mixed withsome of the 2-methyl isomer,

CH3 CH3 CHA JH dH-OH, H, N-cmofionomN NCHO 0112011, 0112011, mixed withsome of the Z-methyl isomer, and

CHlCHg 112 on, N-CH CHOHCH N NCHO 011,0 CH CH are particularly usefulfor gastro-intestinal spasm, the dosage being as previously indicated.

Compounds of the structure not only are useful muscular relaxants butalso are mild tranquilizers. The dosage for such purpose is aspreviously indicated.

The drug r CHI-CH2 CH3-1TT-CH,CHOHCH2N NCHO CHrCH is particularly usefulas a tranquilizer. It has an LD 50 of 350 mg./kg. It may be made up inaqueous solution as the hydrochloride to a concentration of free base of50 mg./ml. Orally, it may be used in capsules as the free base in 50%sesame oil or as an acid addition salt, i.e., as the hydrochloride.

Compounds of structure CH CHICK 3) x1 O NCHgCHOHCHzN NCHO CHzCHg relievecoughs caused by minor irritation of the lungs, the dosage being thesame as recited in connection with the motor relaxants previouslymentioned.

An important use of compounds of structure is based on the fact thatthey can be hydrolyzed to form the useful intermediates of the structureB-omoHoHomN N -11 (III) some cases. Cleavage of the formyl group fromcompounds of structure (IV) can be carried out by heating withhydrochloric acid. A convenient solution for this purpose is 2 Nhydrochloric acid but more dilute or more concentrated solutions can beused.

The free bases of structure (HI) are obtained from the reactionmixtures, after acid hydrolysis, by treatment with excess sodiumhydroxide solution. For the isolation of free bases of very lowmolecular weight, which are very soluble in water, evaporation of theacid solution to low volume before treatment with base greatly increasesthe yield. Also, regardless of the method of hydrolysis, the solubilityof the free base of structure (III) in water can be decreasedappreciably by the addition of solid sodium hydroxide.

The compounds of structure (IV) which are to be hydrolyzed to (III) canbe prepared either by Equation 4 or Equation 6. Equation 4 is the methodof choice unless B is (CH N, in which case Equation 6 is the preferredmethod of synthesis.

In the preparation of compounds of structure (HI) from (IV), eitherpurified or crude formyl derivatives can be used. Usually, the use ofthe crude product is the method of choice.

Examples 23-28 will illustrate methods of hydrolysis of (IV), suchmethods being exemplified by Equation 7 previously set forth (in certaincases, the description will include details of preparation of thematerials utilized in these methods in accordance with one or more ofthe methods previously described).

EXAMPLE 23 To 13.6 g. (0.05 mole) of 1-formyl-4 (3-diethylamino-Z-hydroxypropyl)-cis-2,5-dimethylpiperazine, in a 500 ml. round bottomflask, was added slowly, with shaking, 200 ml. of 2 N hydrochloric acid.The reaction mixture was refluxed gently for 18 hours on a Glas-col. Thereaction mixture then was cooled and extracted with 200 ml. of ether.The ether extract was discarded and the aqueous layer was made stronglybasic with 6 N sodium hydroxide solution. An oil rose to the surface.This oil was extracted with two 200 ml. portions of ether. The etherextracts were combined and evaporated in a rotary evaporator. The oilyresidue on distillation yielded 1-(3-diethylamino-2-hydroxypropyl)-cis-2,S-dimethylpiperazine, boiling -at 99-100 at 0.15mm. pressure.

A sample of the same 1-formyl-4-(3-diethylamino-2-hydroxypropyl)-cis-2,S-dimethylpiperazine, on being bydrolyzed withaqueous alcoholic sodium hydroxide solution, yielded1-(3-diethy1amino-2-hydroxypropyl)-cis-2,5- dimethylpiperazine, boilingat 101402 at 0.05 mm. pressure. The identity of this compound and thecompound just above, boiling at 99-100 at 0.15 mm. pressure, was provedby the infrared spectra of the two samples.

EXAMPLE 24 1-(3-di-n-propylamino 2 hydroxypropyl)cis-2,5-dimethylpiperazine, boiling at 136139 at 0.90 mm. pressure, wasobtained by hydrolysis of 1-formyl-4-(3-di-npropylamino-Z-hydroxypropyl-cis-2,5-dimethylpiperazine in about ten volumes of aqueous potash (23%by weight).

EXAMPLE 25 A mixture of 0.20 mole each of1-formyl-cis-2,5-dimethylpiperazine and 3-piperidino-1,2-epoxypropane in150 ml. of ethanol was allowed to stand overnight and was refluxed for 8hours. Then 280 ml. of 2 N hydrochloric acid was added and the refluxingwas continued for 3.5 hours and the alcohol was removed by vacuumevaporation. The residue was treated with excess sodium hydroxidesolution and was extracted with ether. The ether was removed by vacuumevaporation. and the residual liquid was vacuum distilled. The yield ofI-( B-piperidino- Z-hydroxypropyl)-cis-2,5-dimethylpiperazine, boilingat -138 at 0.15 mm., was 33 g.

1 3 EXAMPLE 26 A mixture of 86.6 g. (0.61 mole) of1-fiormyl-cis-2,5-dimethylpiper-azine, 106.8 g. (0.58 mole) of3-di-n-butylamino-1,2-epoxypropane and 1 ml. of 95% ethanol was heatedin a water bath for hours and was allowed to stand at room temperaturefor '10 days before being WOIked up. The reaction mixture was pouredinto 1 liter of water and the oily upper layer was separated anddissolved in 1200 ml. of 2 N hydrochloric acid. The aqueous solution wasrefluxed gently overnight, cooled and extracted with 150 ml. of ether.The ether layer was discarded and the aqueous layer was made stronglybasic with aqueous alkali. The oily layer was extracted into 250 m1. ofether. On vacuum evaporation of the ether and vacuum distillation of theresidue, there was obtained 80 g. of l(3-di-n-butylaminoQ-hydroxypropyl)-cis-2,S-dimethylpiperazine, boiling at220-226 at 29mm. pressure.

EXAMPLE 27 (a) -By reaction of equimolar amounts of l-formyl-cis- 2,5-dimethylpiperazine and 3-morpholino-1,2-expoxypropane in a volume ofalcohol approximately double that of the combined reactants, and byhydrolysis of the formed 1-formyl-4-(3-morpholino 2hydroxypropyl)-cis-2,5-dimethylpiperazine with aqueous alcoholicpotassium hydroxide, 1-( 3 morpholino 2hydroxypropyl)-cis-2,5-dimethylpiperazine, boiling at 221-223 at 28 mm.pressure, was obtained in a yield of 56% (b) Another sample of crude1-fiormyl-4-(3-morpholino-Z-hydroxypropyl)-cis-2,S-dimethylpiperazine,on hydrolysis with approximately 2 molar sulfuric acid and treatmentwith excess base, yielded 1-(3-morpholino-2- hydroxypropyl)-cis 2,5dimethylpiperazine, boiling at 223 at 29 5 mm. pressure.

EXAMPLE 28 1-(3-di-n-butyla rnino 2hydroxypnopyl)-trans-2,5-didimethylpiperazine, boiling at 207-209 at 29'mm. pressure, was obtained from crude1-formyl-4-(3-di-n-butylamino-Z-hydroxypropyl)-trans-2,S-dimethylpiperazine,by hydrolysis with an aqueous-alcohol solution approximately N inhydrochloric acid and. treatment with excess base.

In addition, all of the compounds of structure B-CH2CHOHCH;;N\ N-H ofthe present invention can be prepared by Equation 8, as illustrated inExamples 29 to 39.

EXAMPLE 29 EXAMPLE 30 A mixture of 8.5 g. (0.05 mole) of3-(methylcyclohexylamino)-1,2-epoxypropane, 5.0 g. (0.05 mole) ofZ-methylpiperazine and 25 ml. of 95 ethyl alcohol was allowed to standat room temperature for 4 days and was heated gently on a sand bath for10. hours. On vacuum distillation,- the reaction mixture yielded 7 g. of1-(3- methylcyclohexylamino 2 hydroxypropyl) 3 methylpiperazine (mixedwith some of the Z-methylpiperazine isomer) boiling at 158-163 at 0.20mm. pressure.

EXAMPLE 31 A mixture of 168 g. (1.30 moles) of 3-diethylamino1,2-epoxypropane and 228 g. (2.00 moles) of cis-2,5-dim'ethylpiperazinewas allowed to react in a water bath at 14 30 for 3 hours and then washeated on a steam'bath for 20 hours wth frequent mixing. The reactionmixture was distilled under reduced pressure, yielding 220 g. of 1-(3diethylamino 2 hydroxypropyl)-cis 2,5;dimethylpiperazine, boiling at126-128 at 0.80 mm. pressure.

The compound CH3 cream (C H NCHaCHOHCHzN N-H onion cis was found to beparticularly valuable as a central nervous stimulant. The compoundprepared as above described was occasionally purifiedwith a water pump,but an oil pump, at a recorded pressure of about 0.05 mm. to about 0.80mm., was used most of the time.

In another run, 1-(3-diethylamino-2-hydroxypropyl)-cis-2,5-dimethylpiperazine, prepared as just above, had a boiling point.of 103-106 at 0.11 mm. pressure. A comparison of the infrared spectraof this sample and the samples, boiling at 99-100 at 0.15 mm. pressureand 100102 at 0.05 mm. pressure, prepared in a previous experiment byacid and base hydrolysis of on. on-orn (C HmNCH CHOHCH N NCHO CHaCH (5H3cls proves the identity of the three samples.

' EXAMPLE 32.

A solution of 51.3 g. (0.45 mole) of cis-2,5-dimethylpiperazine and 42.5g. (0.30 mole) of 3-piperidino-1,2- epoxypropane in 100 ml. of 95%ethanol was heated in a water bath at 40 for 5 hours and then at 60-65for 3 hours. On removal of the solvent by vacuum evaporation and onvacuum distillation of the residue there was.

obtained 30 g. of 1-(3-piperidino-2-hydroxypropyl)-cis-2,5-dimethylpiperazine, boiling at approximately 157-160" at 0.20 mm.pressure.

EXAMPLE 33 To 362 ml. of an ether solution of 1.00 mole of crude3-diniethylamino-1,2-epoxypropane was added slowly, with shaking, 171 g.(1.50 mole) of cis-2,5-dimethylpiperazine. After one hour, ml. of 95%ethanol was added. The reaction mixture was allowed to stand for 2 days.Volatile solvents were removed in an evacuated rotary evaporator. Theresidue, on vacuum distillation, yielded 42 g. of1-(3-dimethylamino-2-hydroxypropyl)- cis-2,5-dimethylpiperazine, boilingat approximately 104- 108 at 0.32 mm. pressure.

EXAMPLE 34 A mixture of 8.58 g. (0.060 mole) of 3-morph-olino-1,2-epoxypropane and 11.44 g. (0.080 mole) of 2,3,5,6-.

tetramethylpiperazine was allowed to stand overnight and then was heatedon a steam bath for 30 hours. On vacuum distillation of the reactionproduct, there was obtained 13.5 g. of 1(3-morpholino-2-hydroxypropyl)-2,3,5,6- tetramethylpiperazine, boilingat approximately 158-159 at 0.35 mm. pressure.

EXAMPLE 36 A mixture of 156 g. (1.0 mole) of3-(4-methylpiperazino-l,2-epoxypropane and 228 g. (2.0 mole) of cis-2,S-dimethylpiperazine in a 1 liter flask was allowed to stand, withoccasional shaking for 11 days. At the end of this time the reactionmixture had become very viscous. It was then heated for 8.5 hours withoccasional shaking, on a water bath at 80". On vacuum distillation,there was obtained 174 g. of I CH3 021,011. I 011-011,

011.: Nomononomu N-H 011,0 onion 1 Table B Compound Yield,

percent 01120 Hz CHzCHg CHaN NCHzCHOHCH2N N-H 42 CHzCHa CH CHz CH; CHzCH: CHzC JTI CH N NCHzCHOHCHzN N-n 64 0112011, onion,

(with some of the Z-methyl isomer) CH: CHzO Hz (kH-CH:

CHzN NCHzCHOHGHzN N-H 44 CHzCHz CH CH trans (3H CH3 CHzCHg CHzH CHaNNGHZCHOHOHZN NH 75 CHzCHz CHzCH (with some of the 2,6-dimethyl isomer)CH3 CH CHnCHn CH-(JH CHiN NCHzCHOHCHzN N-H 30 CHzC a OHCH C H; C Ha Theboiling points and analyses of these dipipe razinopropanols are given inTable C.

10 EXAMPLE 37 To 8.0 g. (0.04 mole) of crude 3-(4-butylpiper'azino)-1,2-epoxypropane in 50 ml. of ether was added 9.0 g. (0.079 mole) ofcis-2,S-dimethylpiperazine. The products were mixed thoroughly and'wereleft standing in an uncovered flask for 3 days and then were heatedgently on a sand bath for 5 hours. The reaction mixture then wasdissolved in ether and the insoluble residue was discarded. The etherwas evaporated and the oily residue was vacuum distilled. The yield ofCHzCHz H-CH1 CH CH CH CH N NGH CHOHCH N NH CH CH CH CH cls CH3 boilingat 160170 at 0.20 mm. pressure, was 6.0 g.

EXAMPLE 38 i To 7.1 g. (0.030 mole) of crude3-(4-n-hexyl-2-methylpiperazino)-l,2-epoxypropane in 50 ml. of ether wasadded 7.0 g. (0.067 mole) of 2,6-dimethylpiperazine.v The products weremixed thoroughly and were left standing in an open flask for 3 days.Then the mixture was heated gently on a sand bath for 1 day. The mixturewas dissolved in ethanol, treated with excess sodium hydroxide solutionand extracted with ether. 0n evaporation of the ether and vacuumdistillation of the residue,

there was obtained 2.5 g. of

CH3 CH3 0112011 OH,( H

CHgCH CHgOH ClLCIhN NCH CHOHCHzN N-H H9 H CH1 H boiling at ISO-190 at0.28 mm. pressure. There were also traces of other isomers present.

EXAMPLE 39 (a) The bis-piperazinopropanol, mainly of the structure CH;011. on.

, omt'lrr 11-011 01130112011: NGH CHOHCH N \NH 0112011 ctr-0Q Ha a aboiling at approximately -170 at 0.15 mm. pressure, was obtained in ayield of 26% by the following procedure:

A mixture of approximately equimolar quantities of crude2,6-dimethyl-4-n-proply-1-(2,3-epoxypropyl)-piperazine and2,3,5,6-tetramethylpiperazine was allowed to stand at room temperaturefor two weeks with frequent mixing and then was heated on a water bathfor 16 hours. The reaction mixture was extracted with ether and theethereal extract was dried over solid potassium carbonate. The ether wasvacuum evaporated and the residue was vacuum distilled.

(b) Similarly,

boiling at 160-175 at 0.20 mm. pressure, was obtained from crude4-n-butyl-2,3,5,6-tetramethyl-1-(2,3-epoxypropyl)-piperazine and2,6-dimethylpiperazine.

plied Found 20 655 05 1 157 346102148305301200 08911 068 5 w nozuwWWW--89Q2W%M%%%%%13UWWM253609255007354 5858 59158 9354 9 Nitrogen. percentCalcd.

025510000050005550 20558 00055 mummmmwmwemmamaemummemmeawm i018912215491 z 2 3 .17 Q2QQQQQQQNQQQQQQQQQQQQQQQQQIQQQOQQOOOOOO000000 02000 18 2,3epoxypropyl)piperazine and us in compounds of the skeleton I -C--N 1'1The nitrogen content of these dimethyl-4-n-propy1-1-(Z-methylpiperazine.

In addition to the foregoing methods of preparation of compounds (III),such compounds may .also be prepared alkanol piperazines disclosed inapplicants Patent No. 3,015,657, issued January 2, 1962. l

I Early in the present work, titrations of the amines were carried outin GH solvent (a solution of ethylene glycol two of the three nitrog'estructure H NG- are titrated. in later Work, titrations were carried outwith perchloric acid in glacial acetic acid, a reagent which titratesall of the nitrogens in compounds of structure 20 (III). The latterreagent was used for all of the titrations in Table C except whereotherwise indicated. To avoid confusion, the compounds titrated in GRsolvent are listed at the end of Table C. compounds reported ascalculated should be multi ,6- 25 by 1.5 to get the total nitrogenpresent.

Table C B-CH OHOHOH N 306802689550552631740 37400 58084mmeawewmanaaaemjamnmaaeea555000023446444565567 ti nmwwn 3 i 4 4 3 j ajji jfifi awi au mwwameew wmmnwaamaemewoeem emas mews;

t 5 by hydrolysis in acid solution of the carbalkoxyaminoa CH3 CH3(BE-CH CH,CHOHCHN\ cis A slight variation in the i /CH2CH NCHnCHOHCH2N\cmo CH O (c) The compound,

CH CH $56 CH CH OHzOHgN N old-(3E $113 CH3 boiling at 160-163 at 0.12mm. pressure, was obtained 10 and isopropanol in ratio of In thisSolvent, 3 from crude 4-n-butyl-2,3,5,6-tetramethyl-1-(2,3-epoxypropyl)piperazine and 2,6-dirnethylpiperazine by approximately the sameprocedure. isolation of the bis-piperazinopropanol involved the additionof sodium hydroxide solution to the reaction mixture 15 before the etherextraction.

(d) The bis-piperazinopropanol, mainly of the structure CH3 /CHzsCHzCHgCHgN boiling at 154-157 at 0.15 mm., was obtained from 2 Seefootnotes at end of table.

Table CCont1nued Nitrogen, percent 11 B B.P., Pressure,

Calcd. Found Piperidino 0. 08 14. 82 14. 79 2-mcthylpiperidino O. 35 14.12 14. 3 methylpiperidino 0. 40 14.12 13.72 4-methylpipcridino. 0. 5O14. 12 13.88 2,6-dimcthylpipcridino 152-155 0. 13. 49 13. 02l\lethylcyclohcxylamino 158-160 0. 13. 49 12. 97 Morpholino 158-159 0.14. 72 14. 80 4-metl1ylpipcrazino 153-156 0. 35 1.8. 73 18. 18 4n-pr0pyl-2,6-dimethyl perazino 160-170 0.15 15. 80 15. Di-n-butylamiuo220-226 29. 0 B 9. 35 h 9. 15 29. 5 B 10.90 h 10. 42 28.0 s 10. 90 h 10.60 29.0 9. 35 9. 23 0.15 8 10.96 11 10.63

NOTE.--All compounds in Table 0 were prepared by Equation 8 unlessotherwise indicated.

B Prepared by acid hydrolysis of a compound of structure (IV). bPrepared by basic hydrolysis of a compound of structure (IV).

" Titrated with perchloric acid in glacial acetic acid, unless otherwiseindicated.

h Titrated with hydrochloric acid in GE solvent (ethylene glycol andisopropenol, 1/1).

The compounds of structure (III), which can be formed as aforesaidthrough the hydrolysis of compounds of structure (IV), afford theorganic chemist most useful and active intermediates to react with anyLewis acid which acts preferentially with the group NH rather than witha tertiary amino or secondary alcoholic hydroxyl group. Epihydrinamine,other 1,2-epoxides, 1,2- chlorohydrins, aryl sulfonyl chlorides and arylisothiocyanates react readily and preferentially with the secondaryamino group in (III). Under controlled conditions, aryl isocyanates andhigh molecular weight acid chlorides, such as diphenylacetyl chloride,react preferentially with the secondary amino group in (III).

Also, many other Lewis acids well known to the organic chemist reactpreferentially with the secondary amino group in (III). Thus, thecompounds of structure (III) afford the organic chemist a synthesis,usually in one step, of a wide variety of useful chemicals.

In addition to the foregoing, compounds of structure (III) are useful asintermediates in the formation of medicinal products such as bronchialdilators, as described in applicants Patent 3,037,983.

The present invention is concerned only with the compounds of structure(IV) and structure (III) and not with derivatives of either structure.Therefore, data on reactions of these compounds will be given only todemonstrate their utility.

Compounds of structure (III), on reaction with CH (CH CHOHCH Br, formether-soluble products of very low water solubility of the structure.

ongormriononomri NcmoHonom-B (CHa) n (V) can be prepared by the reactionof 1-bromo-2-octadecanol and the alkanolamines of structure (III) byprolonged heating at about A typical synthesis and purification of theproduct of structure (V) is given below:

EXAMPLE 40 A mixture of 69.6 g. (0.20 mole) of 1-bromo-2-octadecanol and54.2 g. (0.20 mole) of l-[3-(di-n-propylamino)-2-hydroxypropyl]-cis-2,5-dimethylpiperazine was heated at approximately100 for 40 hours in a sealed glass tube. The gummy product was dissolvedout of the tube with 75 ml. of hot 12 N hydrochloric acid. The reactionmixture was made basic with sodium hydroxide solution and extracted withapproximately 750 ml. of ether. The aqueous layer was discarded and theether layer was treated with 60 ml. of 12 N hydrochloric acid. Asemisolid was obtained. The ether was decanted off and the residue wastriturated twice with 300 ml. of ether and twice with ml. of ether. Thesemisolid then was dissolved in 1 liter of water and the solution wasmade basic. An oil came to the surface. The oily layer, which containedan appreciable amount of ether, was separated and was treated with 40ml. of 12 N hydrochloric acid and 375 ml. of ether. Again a semisolidwas formed. The ether was decanted off and the semisolid was dissolvedin 2 liters of water. The aqueous solution was made basic and an oilcame to the surface. This layer was removed and the lower layer wasextracted with 375 ml. of ether. This ether layer and the upper layerjust previously removed werecombined, filtered and dried over sodiumpotassium carbonate. On evaporation of the ether in a rotary evaporator,25 .3 g. of oil, crude CH3CH3CH1 H-CH;

NCHgCHOHCHgN N--CH;OHOH(CH5)15CHI C H 0 H 0 3 C HgC cis H;

was obtained. (Calcd. for C H N O N, 7.73. Found: N, 8.29.) The nitrogenwas determined by titration with perchloric acid in glacial acetic acidsolution.

In most of the preparations, removal of the basic nitrogen containingcompounds of structure (V) from other ether soluble material, likely thebromohydrin or glycol of octadecene, proved to be quite difficult. Thus,usually the nitrogen analyses were low, even though in some casesadditional extractions were made into ether and from the ether back intoaqueous hydrochloric acid solution. The great tendency of the highmolecular weight alkanolamine hydrochlorides to form aqueous-etheremulsions made quantitative separations difficult.

The high analyses obtained in a few cases probably CHa(C z)1aCHOHCH NNOH CHOHOH -B n B Molecular Nitrogen, percent formula Caled. Found A(H-ClHnhN CaaHwNs02 7. 78 8. 33

C H H-CH:

1 O N C32Hu NsOa. 7. 78 7. 69

CH-CHr 2 (CHahN UzoHarNaOz. 8. 69 8. 2].

CH AXE-CH2 2 0 N caaHmNaoahn. 7. 56 7.29

CH-Cfi2 2 (O2H5)2N CarHo5N302. 8. 21 9. 22

CHaCHr 2 O C 1H NaO3- 7. 99 7.01

CHzCE b p CHaCHn 2 C HaN N CazHaaN40z 10. 60 9. 62

CH CHQ 2 (CH3)2N Cr9Ha1N30a 8. 69 7. 64

4 (CHshN Cs H 5N3O2 8. 20 7. 05

Nitrogen titrated with perehloric acid in glacial acetic acid. bZ-methylpiperazine used in synthesis.

0 Trans-2,5-dimethy1piperazine used in synthesis.

d Ois-2,5-dimethylpiperazine used in synthesis.

2,6-dimethylpiperazine used in synthesis.

esters which, on hydrolysis withsodium hydroxide, form sodium salts ofstructure which can be deposited from aqueous solution in cotton cordand cotton cloth. The impregnated cloth and cord, on being treated withCu(NH SO and dried, have relatively insoluble copper chelates dispersedthroughout the material. These copper-containing chelates, prepared fromcompounds of structure (III), form valuable mildew-proofing agents.Details of tests with copper chelates of (VI) will'be hereinafter setforth.

Compounds of structure (VI) may be prepared by the following typereactions:

(out).

\N H BrCH OHOH(CH2)aC O O CH;

n-omorrononm is given below:

EXAMPLE 41 A mixture of 27.0 g. (0.10 mole) of1.-[3-(4-methylpiperazino)-2-hydroxypropyl]-cis 2,5 dimethylpiperazineand 29.5 g. (0.10 mole) of methyl 11-bromo-10- hydroxyundecanoate washeated at approximately 100 in an oil bath for 16 hours. The reactionmixture was dissolved in 150 ml. of 6N hydrochloric acid and dilutedwith water to 800 ml. On treatment with excess 6 N sodium hydroxidesolution, an oil separated. The reaction mixture was extracted twicewith 150 ml. portions of ether and the combined ether extracts weretreated with 16 ml. of concentrated hydrochloric acid to yield a loweroily layer. The ether was decanted off and the oily layer was trituratedfour times with 75 ml. of ether. The oily layer was dissolvedinapproximately 400 ml. of water. 0n addition of excess sodium hydroxidesolution, an oil separated. This oil was dissolved by extraction twicewith 150 m1. portions of ether. The combined ether extracts were washedtwice with 500 ml. portions of water, filtered and dried over solidpotassium carbonate. On evaporation of the ether, the crudepolyaminoalkanol ester CHaCHa THE-CH1 QH3N/ CHgOHOHCHgN NCHgOHOH(CH)aCOOCHs omen. onion eis H3 The compounds of structure (III) also reactwith was obtamed as (Calcd' for C25I-{52N-4O4: z w flfl s to yieldalkan01amino 11,85 Found. N, 10.l3%.) On sapomficatron withaqueous-alcohohc sodrum hydroxide solution, the salt GHQCHZ H-CH;

CHEN NCHzCHOHCHz NCHQCHOHUJHDBCOONQ The effectiveness of the copperchelates of (V) and (VI) as fungicidal agents is demonstrated readily byimpregnation of cotton cloth and cotton cord with these compounds and byexposure of the impregnated cellulosic material to the fungus,Chaetomium globosum. The reasons for the choice of this particularfungus for the test organism are set forth in the American DyestuifReporter, 23, 586 (1934); Technical Bulletin No. 726 of the UnitedStates Department of Agriculture, page 2 (March 1940).

Details of tests with Chaetomium globosum on cotton cloth and cottoncord, impregnated with copper chelates of compounds of structure (V) andcontrols, not impregnated, are given below.

The basal medium used in the tests contained essential inorganicmaterial and agar dissolved in distilled water. The carbon source forthe fungus was the cloth or cord, placed on the surface of thesolidified medium in Petri dishes. Inoculum consisted of a sporesuspension of Chaetomium globosum in distilled water. The inoculum waspipetted uniformly over the surface of the test cloth the test cord.Cultures were incubated at approximately 25.

A piece of cotton cloth was impregnated with another solution containingapproximately 7% by weight of CH: JJH-C H2 NCHzCHOHCH N CHrCH cis andwas air dried. The cloth then was immersed in a solution approximately0.25 N in ammonium hydroxide containing 1 gram of CuSO -5H O in 100 ml.of solution and allowed to dry. It was then washed and again allowed todry.

The impregnated cloth and a control (a similar piece of cloth, notimpregnated with alkanolamine and copper salt) were placed on agar inseparate Petri dishes and treated with the suspension of Chaetomiumglobosum, as indicated above.

At the end of four days incubation, the control cloth was covered withabundant vegetative growth and at the end of two weeks, was completelycovered with large perithecia. Deterioration was so far advanced that itwas impossible to remove the cloth from the surface by the agar; thecloth, in fact, had been almost completely replaced by fungus growth.The treated cloth, after two weeks, displayed only trace amounts ofvegetative growth and a few, widely scattered, small perithecia, with nosigns of advanced deterioration. 7

The breaking strength of a sample of cotton cord was determined byadding water from a graduated cylinder to a container suspended by thecord, until it broke. Pieces of cord from the same ball were immersed ineither solutions of compounds of structure (V) containing approximately7% by weight of (V). After air drying, the pieces of cord were immersedin solutions approximately 0.25 N in ammonium hydroxide and containing1.0 g. of CuSO -5H O per 100 ml. of solution. The cords were air dried,washed and again air dried. The break- CH3 (CH CHOHC HgN ing strength ofthe impregnated cords then was detersamples were determined. This amountwas expressed in' a 24 percent of total weight of cord, alkanolamine andcopper salt.

The data are given below in Table B.

Table E ICOMPOUND (V) r 7 OH-CH CHzCH:

C H CHOHCH NCHflCHOHCHgN NCH;

CHflIJH CHzC 3 cis Breaking strength after 11 Percent Breaking strengthdays copper in cord , CHQOHE CHgCHgCHgOHa CmHaaCHOHCHzN N CHQCHOHCHZCHQCH: CH CH CH CH Breaking strength after 11 Percent Breaking strengthdays copper in cord C H3 0 H3 H-C H1 H-C H, O H CHOHCBQN NCHQCHOHCH: OH;

' CHQC CHgCfig cis Breaking strength after 11 Percent Breaking strengthdays copper in cord 8,927 g 6,887 g 0. 78 N one (control cord) 7,714 g1,004 g None Norm-The copper was determined by extraction of the cordwith 1.5 N nitric acid, evaporation of the solution, ignition of theresidue, solution of the residue in nitric acid, dilution, adjustment ofthe pH to approximately 6.0, addition of ethylene diamine andspectrophotometric measurements of the color.

In another test, using CH2 ill-CH OH GH CH; OH;(CH:)15CHOHCH N NCHzCHOHCH CH O CH CH CH;

cis

to impregnate the cord, the breaking strength of the cord initially wasapproximately 8110 g. and after 11 days incubation with Chaetomiumglobosum, the breaking strength of the cord was approximately 8299 g.The slight increase in breaking strength of two samples of cord, above,is probably due to variations in the cord.

As is noted, the untreated cord lost approximately of its strength. Twopieces of treated cord showed no loss in strength. One piece lostapproximately 4% of its strength and another piece of cord lostapproximately 23% of its strength.

In another series of tests, with another ball of cord and apparentlywith a more active culture of Chaetomium globosum, an untreated cordwith a breaking strength of approximately 5961 g. dropped toapproximately 315 g.

in 12 days. 'Iwo samples of cord were impregnated with H-GH: CH20H|CH3(CH2)1BOHOHOH2 NCHaCHOHCHzN CHROH \CH2CH:

and then with ammoniacal copper sulfate. After 12 days, one sample had abreaking strength of approximately 5551 g. or approximately a loss of 7%in breaking strength and the other sample showed no decrease instrength. As is noted above, the untreated cord lost approximately 95%of its strength.

In another test, a cotton cloth was impregnated with H-CH, 011,011,011.CH (CHq)r5CHOHCH2N NCHaCHOHCHgN CH G CHi N I eis (1.0 g. in 20 ml. ofether solution) and was air dried. The cloth then was immersed in asolution approximately 0.25 normal in ammonium hydroxide and containing1.0 g. of CuSO -5H O in 100 ml. of solution. It then was washed bydipping ten times in fresh water and was air dried. The copper was foundto be approximately 0.48% of the total weight of cloth, alkanolamine andcopper salt. The cloth then was immersed for eight days in a beaker intowhich water was slowly running. After air drying the copper content ofthe cloth was approximately 0.40%.

Compounds of the structure impregnated intocloths, form relativelyinsoluble chelates when immersed in ammoniacal solutions of C++ and ofNi++.

The same general procedure, with slight modification, was used to testthe fungicidal effect of copper chelates of compounds of the structurein protecting cotton cord from the action of Chaetomium globosum. A cordwith a breaking strength of 8430 g. was used in these .tests.

In each test, the cord, washed with ether to remove any oils which mightbe present, was immersed in approximately 1% aqueous solution of thecompound of structure (VI). The cord was air dried, immersed in asolution approximately 0.25 N in ammonium hydroxide and containing 1.0g. of CuSO '5H 0 per 100 ml. of solution. The cord was air dried, washedfor one hour in gently running tap water and again air dried.

Treated and untreated cord were placed in separate Petri dishes on thesame type solid medium used in the previous tests. As before, theinoculum of a suspension of Chaetomium globosum was pipetted uniformlyover the impregnated cord and control. Incubation at 25 was carried outfor 14 days. The control cord was almost completely disintegrated by theaction of the fungus. The breaking strength of this cord was so low itcould not be measured.

Data are given below in Table F on treated cords and the control cord.The breaking strength is the average of four or five tests.

Table F O OMPO UND (V 1) HC\H1 01H: Na0OC(CH2)a HOHCH:N NCHQCHOHCHgN01136 H CgHg cis Breaking strength of cord after 14 days Copper, percent(in cord) s (a) CH-CHQ CHQOH] NaOOC(OHa)rCHOHCHgl N CHQCHOHCHgN NCH CHCH GH C g cis Breaking strength of cord after 14 days Copper, percent(in cord) H-CH, CHgCHgCH: NaOOC(CH3)3CHOHCH:N NCHgCHOHCHz.

CH O GH CH OHs cis Breaking strength of cord after 14 days Copper,percent (in cord) 7,684 g y I 0.83

(a) On one of the two plates used for the test with this compound, therewas at the end of the test period (14 days) an appreciable growth ofChaetomtum qlobosu-m, and in spots practically complete diisntegrationof the cord. The data reported are the average of four determinations ofbreaking strength of cord from another plate and from places on thisplate where the fungus had not grown.

As is evident in the prolonged test reported just above, the copperchelates of compounds of structure (VI) did not give the cord completeprotection from Chaetomium globosum, but in five out of six plates therewas a maximum loss in breaking strength of less than 10% and in thesixth plate, the growth of fungus was distinctly less than in thecontrol. p p

A sampleof cotton cloth was impregnated with an approximately 1%solution of C H: V

. 114311. 013,011,011, Naooownnscnononm NCH OHOHCH N 011,0 ornomon,

ois

air dried and impregnated with approximately 1% CuSO -5H O inapproximately 0.25 N ammonium hydroxide. After air drying, the cloth waswashed for one hour in gently running tap water. The copper content ofthe cloth was 0.41%. On being washed for 3 days in gently running water,the copper content was 0.37%. After one week in running water, thecoppercontent of the cloth was 0.33%.

Other uses of the compounds of structure (III), as intermediates for theformation of chelating agents, will occur to those persons skilled inorganic synthesis. For example, all of the derivatives of (III), formedby the reaction of of the secondary amino group only, contain from twoto four basic nitrogens, each so situated spatially that it ispotentially capable of chelating with cations such as Cu++, Co++, Ni++and Zn++, which readily form ammonia complexes.

The compounds formed by reaction of a halohydrin or epoxide with the NHgroup of (III) have one hydroxyl group which is two carbons removed fromtwo basic nitrogen and one hydroxyl group which is two carbons removedfrom one basic nitrogen. In cases when epihydrinamines of structure(wherein R is a lower alkyl group) react with the NH group of (III), thefollowing structure is formed:

RzNCHgCHOHCHgN NCH CHOHCHzN In the above type compound, each hydroxylgroup is two carbons removed on each side from a basic nitrogen atom..

H-N NOH CHOHCHaB in which B is an alkylpiperazine coming within thescope of the present invention have the structure (R' being a loweralkyl group) in which there are five nitrogen atoms properly spaced forchelation.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. For example, whilethe member B in structure (I) is set forth as being various heterocyclicradicals, such radicals may be substituted without changing the basicnature of the compounds of the instant invention. Merely by way ofexample, the lower alkyl derivatives of the piperidino radical may beemployed. Other modifications will readily suggest themselves to thoseskilled in the art. The present embodiments are therefore to beconsidered in all respects as illustrative and not restrictive, thescope of the invention being indicated by the appended claims ratherthan by the foregoing description, and all changes which come within themeaning and range of equivalency of the claims are therefore intended tobe embraced therein.

We claim:

1. A compound of the structure B-CHzCHOHCILN NX (I) wherein B is amember of the group consisting of mor- .28 pholino, pyrrolidino,piperidino, methylcyclohexylamino, piperazino of the structure Y-N N-wherein Y is an alkyl radical of 1 to 6 carbons, and

wherein R and R each is an alkyl radical of 1 to 4 carbons; wherein X isa member of the group consisting of Hand CHO; andn is a number from 0 to4 both in structures (I) and (II); no carbon in the piperazine rings ofstructures (1) and (11) having more than one methyl group attached toit.

2. A compound selected from the group of compounds consisting of (1)compounds of the structure wherein B is a member of the group consistingof morpholino, pyrrolidino, piperidino, monomethylpiperidino,2,6-dimethylpiperidino, methylcyclohexylamino,

wherein R and R each is an alkyl radical of 1 to4 carbons; and n is anumber from 0 to 4; no carbon in the piperazine ring having more thanone methyl group attached to it; and (2) the therapeutically acceptableacid addition salts of compounds (1).

3. A compound of the structure wherein B is a member of the groupconsisting of morpholino, pyrrolidino, piperidino,methylcyclohexylamino, piperazine of the structure wherein Y is an alkylradical of 1 to 6 carbons, and

CH; IE-CH: CH IITCH CHOHCH N NCHO CHgO 20 s 5. A therapeuticallyacceptable acid addition salt of 10. The compound the compound of claim4. 311:

6. The compound CHZCH2 CECE:

H3 5 CH3N NCH GHOHCH -N N-H CHI-CE: CH CH CHgOH (CgHOzNCHzCHOHCHgN NOHOCH8 CHZC 0i! 11. The compound CH3 10 CH3 cis I 011-011, (c H) NCH OHOHCHN N-'H 7. A therapeutically acceptable acid addition salt of 2 2 thecompound of claim 6. CECE 8. The compound CH;

eis

References Cited by the Examiner OHQCH" UNITED STATES PATENTS CH4NOHZOHOHOHW NOHO 2,794,804 6/57 Kushner et a1. 260-268 ma, 7 (ma2,948,722 8/60 Biel 260268 X (IDES 2,948,746 8/60 Stuehmer et a1 260268X as 3,015,657 1/62 Geschickter et al. 260-268 X IRVING MARCUS, PrimaryExaminer.

9. A therapeutically acceptable acid addition salt of DUVAL T,MCCUTCHEN, NICHOLAS S. RIZZO,

Examiners.

the compound of claim 8.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,190,883 June 22, 1965 Charles F. Geschickter et al It is herebcertified that error appears in the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 1, lines 16 to 19, for the right-hand portion of formula (1)reading a N-Y read N-X column 2, line 44, for "reaction" read reactionscolumn 5, lines 71 to 75, for the lower right-hand portion of theformula reading CH CH read CH CH column 7, line 38, for "2l62l0" read2l6-2l9 column 9, Table A, second column, line 31 thereof, for "do" readMorpholino same table, third column, line 31 thereof, for "l822l85" readl82-l85 same table, second column, line 40 thereof, for "do" readDiethylamino same table, footnote "d" thereof, for "6-methyl" read6'-dim'ethyl column 11, lines 1 and 7, for "mixed with some of the 2-methyl isomer,", each occurrence, read (mixed with some of the 3-methylisomer,) column 14, line 2 for "wth" read with column 18, Table C,second column, lines 31 to 33 thereof, for "Dielhylamino", eachoccurrence, read Diethylamino column 20', line 52, for "sodium" readsolid column 22, line 66, for "ll,85%" read 11.85% column 23, line 22,for "the" read and line 50, for "by" read of same column 23, line 75,for "were" read was column 26, line 46, for "diisntegration" readdisintegration column 27, line 5, strike out "of".

Signed and sealed this 29th day of March 1966.

(SEAL) \ttest-z ERNEST W. SWIDER EDWARD J. BRENNER \ttesting OfficerCommissioner of Patents

1. A COMPOUND OF THE STRUCTURE